Efficacy of probiotics in pediatric atopic dermatitis: A systematic review and meta‐analysis

Abstract Background Atopic dermatitis (AD) is a prevailing skin disease in childhood. Several studies have appraised probiotics as a strategy for treating AD. We aimed to assess the validity of probiotics in the treatment of AD in children. Methods We systematically searched the PubMed/MEDLINE, Embase, Scopus, EBSCO, Web of Science and Cochrane library databases for randomized controlled trials (RCTs) that assessed the effect of probiotic treatment on SCORAD value in pediatric patients with AD compared with a placebo group between 1 January 2010 and 1 January 2023. The risk of bias and the certainty of evidence were assessed using Cochrane ROB 2.0. Results A total of 10 outcomes from 9 RCTs involving 1000 patients were included. Three of these outcomes were analyzed as dichotomous variables in 373 patients. The other seven were analyzed for continuous variables in 627 patients. A meta‐analysis of the random‐effect model of the dichotomous variables demonstrated no significant difference between the probiotic and control groups [OR = 1.75, 95% confidence interval (CI) (0.70, 4.35), p = 0.23, I 2 = 68%]. A meta‐analysis of the random‐effect model of continuous variables demonstrated significant differences between the probiotic and control groups [MD = −4.24, 95% CI (−7.78, −0.71), p = 0.002, I 2 = 71%]. Subgroup analysis of continuous variables showed that the effects of children's age, treatment duration and probiotic species on the SCORAD value were not statistically significant. Conclusion Evidence on the improvement effect of probiotics on pediatric patients with AD is limited. This study showed that single‐strain probiotic treatment exerts a positive effect on AD. Restricted to the quantity and quality of incorporated studies, these conclusions have yet to be validated by high‐quality studies.


| INTRODUCTION
Atopic dermatitis (AD) is a common inflammatory disease and the most prevalent chronic inflammatory skin disorder in children. 1,2 Its symptoms, including skin scratches and itching at night, considerably affect the quality of lives of children and their families. 3 The incidence of AD has accelerated globally in the last decade, with approximately 10%-20% of children in developed countries living with the disease. 4,5 AD usually appears in early infancy and childhood. Diet, breastfeeding rates, and sanitation are critical factors in the progress of atopic diseases. 6,7 Microbiota dysbiosis is influenced by different environmental factors, including diet and Vitamin D (VD) exposure and intake. Maternal prenatal nutrition and dietary diversity are key factors in child development. The worldwide increase in allergic diseases parallels the prevalence of VD deficiency in Western countries, supporting the hypothesis that VD influences allergy development. VD levels are affected not only by sun exposure but also by diet, making it an important modifiable factor for allergy prevention. 8 Similarly, the gut microbiota is thought to play a crucial part in the pathogenesis of atomicity. 9,10 Maintaining the structural diversity of the gut microbiota can resist the invasion of pathogenic bacteria and reduce the nutrient competition between potentially harmful bacteria and commensal bacteria. Gut microbiota involved in short-chain fatty acid and amino acid metabolism induce maturation of the innate and adaptive immune systems. Thus, the gut microbiota is a potential target for modulating host immune responses. With the development of sequencing technology, many studies have revealed the correlation between gut microbiota and human diseases (including allergic asthma, atopic dermatitis). The "Gut-Skin" axis has been proposed and considered as a new target for the prevention and treatment of AD. 11 Gut microbiota is the most important component of microbial exposure. Therefore, gut microbiota affects the formation of host immune development, and gut microbiota dysbiosis is closely related to immune disorders. Therefore, targeting gut microbiome alterations may be an alternative approach to modulate the immune response and improve skin health in AD patients. 12 In 2001, the World Health Organization defined probiotics as living microorganisms that have beneficial effects on the host when consumed in adequate amounts. 13 16,17 Probiotics may actively fight pathogenic bacteria by secreting antimicrobial factors. They also regulate the immune system and direct it to attack pathogenic microorganisms or promote immune tolerance, thereby reducing inflammation. 18 Strengthening intestinal homeostasis may improve AD, and probiotics are increasingly being used in dermatology.
The application of probiotics to promote the scoring atopic dermatitis (SCORAD) value in children with AD remains controversial, and some studies have suggested that probiotics can effectively improve AD in children. 19,20 Another study found no significant difference between the experimental and placebo groups. 21,22 Therefore, the present work aimed to perform a systematic review and meta-analysis of randomized controlled trials (RCTs) that used probiotics for AD treatment in children. The findings of this work provide evidence for probiotic effects on AD.

| METHODS
This systematic review and meta-analysis is a review of interventions conducted by the Cochrane System Manual and following the Preferred Reporting Item for Systematic Review and Meta-Analysis (PRISMA) guidelines (see Supplementary Material 1). 23 This review has been registered on the PROSPERO (CRD42023407446).

| Eligibility criteria
All RCTs that evaluated the efficacy of probiotics in AD treatment were included based on the following criteria: (1) Participants aged

| Literature search strategy
The PubMed/MEDLINE, Embase, Scopus, EBSCO, Web of Science and Cochrane library were searched for RCTs (from 1 January 2010 to 1 January 2023). To search as comprehensively as possible, we applied a combination of free word and medical subject terms using the most appropriate Boolean operators to expand the scope of the study and find additional references. Keywords related to AD, probiotics, RCT and children in the title or abstract were searched. Using the PubMed database as an example, the following search terms are employed: Atopic Dermatitis (e.g., "Dermatitis atopic e" or "Dermatitides" or "Neurodermatitis atopic"); Probiotic (e.g., "Probiotics"); Randomized controlled trial (e.g., "Randomized" or "Randomly" or "Clinical trial"). The specific retrieval strategy is displayed in Supplementary Material 2. Two researchers (YXW and XXL) independently assessed all retrieved articles against eligibility criteria. In case of a disagreement, we will discuss it with the team until an agreement has been reached.

| Data extraction
Data extraction was quality checked by two other study authors.
Data from each study were extracted independently by two researchers (XXL and DZY), who then examined each other's results to avoid errors. The researchers used a standardized form of extraction of the article data, with an extraction table documenting the details of the study, including basic article information (author name, publication year, etc.), intervention characteristics (probiotic species, dosage) and placebo use (placebo type and measure).

| Risk of bias assessment
The risk of bias was appraised for the primary outcome of AD using the Cochrane Risk of Bias tool using PRISMA guidelines. Assessments were mainly based on random sequence generation, whether the study used blinding, allocation concealment, completeness of data results, selective reporting of data, results and other sources of bias.
The assessment was answered and explained through the form.

| Statistical analysis
Data analysis was performed using Review Manager version 5.4.1.
For measurement data, the standardized mean difference was used as the effective index, and point estimates and a 95% confidence interval (CI) were given for each effect size. Heterogeneity among the outcomes of the included studies was analyzed using the χ 2 test (the test level was α = 0.1), and the magnitude of heterogeneity was quantitatively judged by I 2 . If the heterogeneity I 2 < 50%, the fixed-effect model was used; if the heterogeneity I 2 > 50%, the random-effect model was used. A descriptive statement of the study results was given when the synthetic analysis was not possible. After calculating the results, the combined results with significant heterogeneity were further subjected to sensitivity analysis, subgroup analysis and meta-regression to help determine the source of heterogeneity. Publication bias testing was performed on outcome indicators with more than 10 included studies. Metaanalysis of random-effect or fixed-effect models was used to estimate combined treatment effects. Subgroup analyses were based on children's age or treatment duration (e.g., ≤3 years or >3 years) and type of probiotics.

| Study selection
A total of 1486 studies were retrieved from the electronic database.
Among these studies, 756 duplicate documents were removed, and included studies are shown in Table 1. Table 1 summarizes the essential characteristics of the included studies. Of the 9 RCTs from 2010 to 2021, 5 used multi-strain mixtures to treat AD, and the other 4 used single-strain interventions. The participants included in the study were children and infants aged 0-18 years, including a premature infant in one study.

| Study characteristics
The most common intervention period in the included studies was 12 weeks. Bifidobacterium lactis is a commonly used probiotic strain, and the doses used for the probiotic strains in the trial population varied. However, 1.0 � 10 10 colony-forming units were the most frequently used dose in the included studies.

| Risk of bias in the included studies
The risk of bias in the studies is presented in Table 2. The included studies were high-quality RCTs, and most of the studies followed high standards: 5 (56%) appropriately generated random sequences, 3 (33%) applied appropriate approaches for allocation concealment, and 9 (100%) used blinding.

| Overall clinical effect
A total of 10 outcomes from 9 RCTs were included. SCORAD was used as the evaluation or outcome index for the included studies. In XUE ET AL.

| Clinical effect by treatment duration
In the meta-analysis of seven continuous variables, two treatment durations emerged, namely 8 and 12 weeks, for which we T A B L E 1 Characteristics of the included studies in the meta-analysis.   which may have been a major source of heterogeneity in effects, considering the imperfect immune system function of this population.

| Sensitivity analysis
The sensitivity analysis of continuous variables was also performed.
After removing the study of Wang, 28  showed no significant differences in the SCORAD values of children treated for less than and more than 6 weeks. No significant correlation was found between age and SCORAD values. Kim et al. 59 performed a subgroup analysis and showed that the improvement in AD is significant when the treatment duration is more than 8 weeks, but not significant when the treatment duration is less than 8 weeks. The heterogeneity of RCTs related to treatment time is not significant, and treatment cycles longer than 8 weeks may have a better effect than treatment cycles shorter than 8 weeks. Zhao et al. 60  included studies did not report allocation concealment, which has a certain risk of bias. Third, the number, types and administration methods of probiotics in different studies may also lead to clinical heterogeneity.

| CONCLUSION
This study showed that single-strain

CONFLICT OF INTEREST STATEMENT
None of the authors have any competing interests to declare.

DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.